Systems for clinical trials

Abstract

The invention provides methods and systems for assessing the efficacy of a pharmaceutical which is putatively disease modifying of a cognitive disorder, for use in the treatment or prophylaxis of that cognitive disorder, the method comprising the steps of: (1) stratifying a subject group into at least 2 sub-groups according to a baseline indicator of likely disease progression, (2) treating members of each subject group with the pharmaceutical for a treatment time frame, (3) deriving psychometric and optionally physiological outcome measures for each treated patient group, (4) comparing the outcomes at (3) with a comparator arm of said sub-groups which is optionally a placebo or minimal efficacy comparator arm, (5) using the comparison in (4) to derive an efficacy measure for the pharmaceutical. The methods and systems of the invention address problems such as low rate of decline over the treatment time-frame of patients who have mild-disease severity at baseline and biased withdrawal, particularly in the placebo / comparator treatment arm.

Description

TECHNICAL FIELD[0001]The present invention relates generally to methods for use in assessing the efficacy of a pharmaceutical treatments for cognitive disorders, particularly in respect of physiological and psychometric outcomes for putatively disease-modifying treatments.BACKGROUND ART[0002]Clinical Trials for Disease Modifying Treatments[0003]3,7-diaminophenothiazine (DAPTZ) compounds including methylthioninium chloride (“MTC”) have previously been shown to inhibit tau protein aggregation and to disrupt the structure of PHFs, and reverse the proteolytic stability of the PHF core (see WO96 / 30766, F Hoffman-La Roche). Such compounds were disclosed for use in the treatment and prophylaxis of various diseases, including Alzheimer's Disease (AD) and Lewy body disease. The rationale for the potential efficacy of DAPTZ compounds in the treatment and prophylaxis of disorders such as AD is based on their ability to act on the primary neurofibrillary pathology of Alzheimer's disease discove...

AI Technical Summary

Benefits of technology

[0029]The present inventors propose that in the early stages of disease, endogenous compensation mechanisms, referred to below as “cognitive reserve” in the case of cognitive disorders, may operate to mask ongoing disease progression, so that subjects may appear not to decline clinically. More specifically, the act of recording the performance of a patient using a standard cognitive assessment instrument provides the subject with a learning experience in respect of the test used which permits the subject to compensate behaviourally for ongoing neurodegeneration.

[0031]However, it is obviously desirable to be able to demonstrate therapeutic efficacy at early disease stages, particularly for a treatment such as rember™ whose primary mode of action is to prevent the neuronal destruction that would otherwise occur as a result of neurofibrillary degeneration, occurring particularly in the medial temporal lobe brain regions.

Problems solved by technology

1. As noted above, one surprising discovery of the present invention is that that the primary trial design assumption was false in the rember™ study, i.e. patients who were CDR-mild at baseline did not significantly decline, although patients who were CDR-moderate declined at a somewhat faster rate than expected. This made it impossible to demonstrate the therapeutic efficacy of rember™ in subjects who were CDR-mild at baseline.

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